The present invention relates to methods and devices for enhancing cellular absorption of a substance delivered into a target region of a patient""s body.
A current standard technique for the delivery of drugs or other substances into the human body is needle injection. A bolus containing the drug is typically injected into muscle or fatty tissue and is then absorbed into the interstitial fluid or directly into the fatty tissue. Over a period of time, the vascular system of the body takes over and flushes the drug out of the interstitial fluid or fat and into the capillaries. From there, the cardiovascular system widely distributes the drug into the rest of the patient""s body.
Newly developed drugs often have application only to specific organs or sections of organs. As such, systemic distribution of the drug throughout the remainder of the body can: (1) dilute very expensive drugs, weakening their effects, (2) generate an effect systemically instead of locally, and (3) widely distribute a drug which may be toxic to other organs in the body. Furthermore, some of the newly developed drugs include DNA in various forms, such DNA being degraded very rapidly by natural mechanisms in the body if delivered systemically, thus preventing a full dose from reaching the designated organ. Accordingly, it would be desirable to provide devices, kits, and methods for delivering such site-specific drugs in a manner which enhances absorption specifically at the site of their delivery into a target region of a patient""s body.
The present invention provides methods, devices, and kits for enhancing cellular absorption of a drug or other substance into a local target region of a patient""s body, thereby avoiding the undesirable effects of the substance being widely dispersed throughout the patient""s body by the patient""s cardiovascular system. By xe2x80x9ccellular absorption,xe2x80x9d it is meant that at least a significant proportion of the total amount of drug delivered to the site is absorbed or otherwise taken up by the cells within or surrounding the target site. The nature of the cells will vary depending on the target site. The cells may be muscle or fat cells receiving transcutaneous, intraoperative, or percutaneous injection. In a preferred aspect of the present invention, these cells comprise the patient""s myocardial tissue. However, the cells may also be endothelial, epithelial, and/or other cells which line the interior or exterior of target organs, or brain cells protected by the blood/brain barrier, or organ cells in general. Lastly, the cells may also be specific organ cells of a target organ.
Specifically, a method is provided for enhancing cellular absorption of a substance, comprising the steps of: (a) delivering the substance to the target tissue region, and (b) directing vibrational energy to the target region, wherein the vibrational energy is of a type and amount sufficient to enhance absorption of the substance into the cells of the target region. In a preferred aspect of the present invention, the vibrational energy has a mechanical index in the range of 0.1 to 20 and a thermal index the range of 0.001 to 4.0. Devices for emitting ultrasonic vibrations of a type and amount sufficient to enhance cellular absorption may comprise a wide variety of known transducer systems, such as piezoelectric and magnetostrictive devices.
The application of such vibrational energy to the target region increases cellular absorption on the order of 5 to 5,000 percent or more for biological reporters such as luciferase gene beta-galactosidase and for drugs such as heparin, probucol, the family of anti-cancer vectors, liposome-complexed plasmid DNA, adeno-associated virus, vascular endothelial growth factors, and naked DNA relative to their uptake in the absence of the vibrational energy.
The present invention will be useful for delivering a wide variety of drugs and other substances to target tissue sites. The substances will usually have a pharmological or biological effect and range from those generally classified as small molecule drugs (usually below 2 kD, more usually below 1 kD), such as hormones, peptides, proteins, nucleic acids, carbohydrates, and the like to those generally classified as large molecule drugs (usually above 200 kD) such as complete strands of DNA. The present invention will be particularly effective in delivering macromolecules such as biologically active proteins and nucleic acids. For delivery to the muscles in general, or the myocardium in particular, useful substances may enhance angiogenesis stimulators, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (BFGF). Other useful substances my include endothelial nitric oxide synthase (eNOS) for inhibiting restenosis, and brain naturatic peptides, and beta-adrenogenic receptors for preventing congestive heart failure. Ultrasound in combination with DNA-based vaccines would enhance protein expression by improving the humoral and cellular immune response.
In a preferred method, the substance is delivered to the target cells. This delivery can be accomplished transcutaneously or percutaneously by way of an injection needle or needles, injected in high-velocity, small-volume jets of delivery fluid, or delivered interoperatively. The substance can also be delivered by a controlled release device such as a microsphere. Substance delivery could also be accomplished by positioning the distal end of a delivery device such as a catheter or hand held device proximal to a target region of tissue, wherein a vibrational energy emitter also being positioned at the distal end of the device. For delivery through the skin or surgical use, the device may be constructed similarly to a syringe having an ultrasonic driver on or near the needle tip. For internal delivery, the device will typically be formed as a catheter for intraluminal or endoscopic introduction to a target site.
By xe2x80x9cdelivery,xe2x80x9d it is meant that the drug or other substance is injected or otherwise physically advanced into a target region of tissue. Injection can be performed with a needle and a pressurized source of the substance, e.g. a syringe. A controlled delivery device or depot containing the drug could also be implanted within the target tissue. Substances of interest will typically be delivered through the internal walls and membranes of organs (particularly the epicardium and endocardium when targeting the myocardium), blood vessels, and the like, as well as through the skin. In some instances, the catheter will be percutaneously introduced to a blood vessel or open body cavity in order to permit access to the internal organs and delivery sites.
The present invention also provides a device for enhancing cellular absorption of a substance delivered to a target tissue region of a patient""s body comprising a substance delivery system and a vibrational energy emitter which is adapted to emit vibrational energy of a type and amount sufficient to enhance cellular absorption at or proximal to the tissue surface. Preferably, the substance delivery system comprises one or more injection needles.
In one embodiment, the injection needle and the ultrasound energy emitter form a small integrated device which is received at the distal end of a catheter. In one aspect of this embodiment, the energy emitter may include one or more vibrational energy emitting transducers received within the injection needle. In various embodiments, the vibrational energy emitter is disposed proximate to the substance delivery system. In certain preferred embodiments, the vibrational energy emitter is mounted directly to the injection needle. The vibrational energy emitter may also be disposed concentrically around the substance delivery system. Specifically, the substance delivery system may comprise an injection needle and the vibrational energy emitter is mounted directly on the injection needle. In various embodiments, the injection needle system comprises a plurality of retractable radially extending injection needles which are positioned at the distal end of a catheter such that when the catheter is received into an intraluminal cavity, the injection needles can be radially extended outward puncturing the wall of the cavity and entering into the underlying tissue. In various preferred embodiments, the vibrational energy emitter emits vibrational energy laterally outward in radial directions away from the distal end of a catheter such that the catheter can be positioned in parallel orientation to the target tissue, such as when the distal end of the catheter is received in a blood vessel or other luminal cavity.
Also, specific embodiments of the present invention may include additional diagnostic, measurement, or monitoring components or capabilities. For example, the device for emitting vibrational energy to the target region may be adapted to detect the net electromechanical impedance of the target tissue in opposition with the vibrational device thus enabling an operator to determine when the distal end of the device contacts the target tissue by observing a change in the effective impedance of the device. Moreover, an echo ranging transducer positioned on the distal end of the catheter or other device can be used to determine the thickness and condition of the target tissue. This can be accomplished by operating the ranging transducer in a pulse echo mode, and characterizing the amplitude, spectral content, and timing of the returning echoes. Furthermore, an electrocardiograph monitoring electrode can optionally be positioned on the distal end of the catheter adjacent the substance delivery system for monitoring potentials in a patients myocardium. This can be useful for providing therapy to the site in the myocardium which is responsible for rhythm abnormalities.
Kits according to the present invention may comprise the delivery devices in combination with instructions for use setting forth any of the above-described methods.